CN110803994B - A kind of synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester - Google Patents

Abstract

The invention provides a synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-ethyl caproate, which comprises the following steps: (1) The isovaleraldehyde and malonic acid react in a choline chloride-urea eutectic solvent to obtain 5-methyl-2-hexenoic acid; (2) Reacting 5-methyl-2-hexenoic acid with absolute ethyl alcohol in a choline chloride-methanesulfonic acid eutectic solvent to obtain 5-methyl-2-hexenoic acid ethyl ester; (3) And reacting the 5-methyl-2-hexenoic acid ethyl ester with nitromethane in a choline chloride-urea eutectic solvent to obtain the 3-nitromethylene-5-methyl-ethyl caproate. The method has the advantages of no need of organic solvent, green, low toxicity, environmental protection, simple operation, simple post treatment, high yield and low cost, and is a green and efficient synthesis method for synthesizing the pregabalin intermediate.

Description

Synthesis of a pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester method

technical field

The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of a pregabalin-containing intermediate.

Background technique

Pregabalin chemical name: (3s)-3-aminomethyl-5-methylhexanoic acid, molecular formula: C ₈ H ₁₇ NO ₂ , structure similar to gabapentin. Compared with gabapentin, pregabalin has the advantages of lower dosage, less frequency of medication and less adverse reactions. Pregabalin has a good therapeutic effect on epilepsy. Studies on various animal epileptic seizure models have shown that pregabalin can significantly prevent epileptic seizures, and its active dose is 3-10 times lower than gabapentin. Because pregabalin has good anticonvulsant, anxiolytic and neuropathic effects, it has been widely used in clinical practice. Therefore, it is of great practical significance to carry out the research on its synthetic method. The structural formula of pregabalin is relatively simple, but there are many intermediates, and the synthesis route is complicated. Most of the solvents used are organic solvents, which are toxic and harmful and cannot be reused. The cost is high, and the reaction time is too long, and the yield is low, which affects its industrial scale-up. .

The invention aims at improving the synthesis conditions of the pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester. The first step is to use DES1 as a solvent and catalyst to synthesize 5-methyl-2-hexenoic acid, which not only simplifies the experimental operation and post-treatment process, but also greatly reduces the cost, is low-toxic and environmentally friendly, and the yield is increased to 95%. Above, the catalyzer can be recycled; the second step takes 5-methyl-2-hexenoic acid and dehydrated alcohol as raw materials, utilizes DES2 to make 5-methyl-2-hexenoic acid ethyl ester as solvent and catalyzer; In three steps, 5-methyl-2-hexenoic acid ethyl ester and nitromethane are used as raw materials, and the intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester is prepared by using DES3. The operation is simple and the reaction The time is short, the yield is high, and the cost is low. The present invention has great significance for solving the synthetic defect of pregabalin intermediate, and the synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester is low in cost, simple in operation and convenient in aftertreatment , high yield, and at the same time, its solvent is green and low-toxic, and the catalyst can be reused, which is suitable for industrial scale-up production.

Contents of the invention

The object of the present invention is to provide a kind of synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester, the method has simple operation, safety, high yield, low reaction cost, The advantages of mild reaction conditions and simple post-treatment.

In order to achieve the above object, the technical scheme adopted in the present invention is:

The structural formula containing 3-nitromethylene-5-methyl-hexanoic acid ethyl ester is:

A synthetic method containing a pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester, comprising the following steps:

The first step: add Amol choline chloride and B mol urea to a dry three-necked flask, heat up to 80°C, and stir magnetically until a colorless transparent liquid is obtained, that is, a deep eutectic solvent: DES1 (choline chloride-urea) , cooled to room temperature; then add Cmol isovaleraldehyde, D mol malonic acid (wherein A:B:C:D=1:2:1:1.0-1.2), warming up to 80 ° C, stirring the reaction, TLC monitoring to the reaction completely. After the reaction, cool to room temperature, add a small amount of water, extract with ethyl acetate, wash the organic layer with water, dry, and evaporate the solvent to obtain a colorless transparent liquid, namely 5-methyl-2-hexenoic acid. The water phase is evaporated to recover DES, which can be reused. The second step: add Emol choline chloride and F mol methanesulfonic acid in a dry three-necked flask, heat up to 80°C, and magnetically stir to obtain a colorless transparent liquid, i.e. a deep eutectic solvent: DES2 (choline chloride- Methanesulfonic acid), cooled to room temperature; Add Gmol 5-methyl-2-hexenoic acid, Hmol absolute ethanol (wherein E:F:G:H=1:2:1:1.0-1.2), be warming up to 80 °C, stir the reaction until the reaction is complete. Cool to room temperature, add a small amount of water, extract with ethyl acetate, wash the organic layers with water, dry, and evaporate the solvent to obtain a colorless transparent liquid, namely ethyl 5-methyl-2-hexenoate. The water phase is evaporated to recover DES, which can be reused. The 3rd step: add 1mol choline chloride in dry there-necked flask, Jmol urea, be warming up to 80 ℃, magnetic stirring is until obtaining colorless transparent liquid, DES3 (choline chloride-urea), is cooled to room temperature; Add Kmol5 -Methyl-2-hexenoic acid ethyl ester, Lmol nitromethane (wherein I:J:K:L=1:2:1:1.0-1.2), warming up to 80°C, stirring the reaction until the reaction is complete, cooling to room temperature. A small amount of water was added, extracted with ethyl acetate, the organic layers were combined, washed with water, dried, and the solvent was distilled off to obtain a light yellow transparent liquid, namely ethyl 3-nitromethylene-5-methyl-hexanoate.

The structural formula of a kind of pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester is:

Said adding distilled water, DES consumption is A mL, distilled water: DES=1.5:1.

Compared with the prior art, the beneficial effects of the present invention are:

The invention provides a synthetic method containing a pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester. In three steps, the first step is to use isovaleraldehyde and malonic acid as raw materials, and DES1 is used as a catalyst and solvent to prepare 5-methyl-2-hexenoic acid; the second step is to use 5-methyl- 2-hexenoic acid and dehydrated alcohol are raw materials, DES2 makes 5-methyl-2-hexenoic acid ethyl ester as catalyst and solvent; The third step, with 5-methyl-2-hexenoic acid ethyl ester and Nitromethane is used as a raw material, and DES3 is used as a catalyst and a solvent to prepare a pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester. The method does not need organic solvents, green, low toxicity, environmental protection, simple operation, mild reaction conditions, simple post-treatment, high yield, low cost, and DES can be recycled, which is a green and efficient synthesis of pregabalin intermediates method.

Description of drawings

Fig. 1 is the ¹ H NMR spectrum of 5-methyl-2-hexenoic acid in Example 1.

Fig. 2 is the ¹ H NMR spectrum of ethyl 5-methyl-2-hexenoate in Example 2.

Fig. 3 is the ¹ H NMR spectrum of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester in Example 3.

Fig. 4 is the impact of the number of repeated uses of DES on the yield of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester.

Detailed ways

Below in conjunction with example the present invention is described in further detail:

The present invention uses isovaleraldehyde and malonic acid as raw materials and DES1 as a catalyst and solvent to prepare 5-methyl-2-hexenoic acid; 5-methyl-2-hexenoic acid and dehydrated alcohol As raw material, DES2 is used as catalyst and solvent to prepare 5-methyl-2-hexenoic acid ethyl ester; With 5-methyl-2-hexenoic acid ethyl ester and nitromethane as raw material, DES3 is used as catalyst and solvent to prepare A pregabalin intermediate 3-nitromethylene-5-methyl-hexanoic acid ethyl ester.

Its reaction formula is as follows:

The synthesis of embodiment 1 5-methyl-2-hexenoic acid:

Add 1.4g (1mol) choline chloride and 1.2g (2mol) urea to a dry three-necked flask, raise the temperature to 80°C, and stir magnetically until a colorless transparent liquid is obtained, that is, the deep eutectic solvent DES1 (choline chloride- urea), cooled to room temperature; then added 0.500g (1mol) isovaleraldehyde, 0.725g (1.2mol) malonic acid, raised the temperature to 80°C, stirred and reacted, monitored by TLC until the reaction was complete. After the reaction, cool to room temperature, add a small amount of water, extract with ethyl acetate, wash the organic layer with water, dry, and evaporate the solvent to obtain a colorless and transparent liquid, namely 5-methyl-2-hexenoic acid, a yellow liquid with a yield of 98 %. The water phase is evaporated to recover DES, which can be reused.

¹ H NMR (400MHz, CDCl ₃ ) δ: 10.31(d,1H),6.95-6.99(m,1H),5.50(s,1H),2.07-21(t,2H),1.60-1.75(m,1H ),0.89-0.96(d,6H).

Example 2 5-methyl-2-hexenoic acid ethyl ester:

Add 1.4g (1mol) choline chloride and 1.92g (2mol) methanesulfonic acid to a dry three-necked flask, heat up to 80°C, and stir magnetically until a colorless transparent liquid is obtained, namely the deep eutectic solvent DES2 (chole chloride base-methanesulfonic acid), cooled to room temperature; added 0.729g (1mol) of 5-methyl-2-hexenoic acid, 0.314g (1.2mol) of absolute ethanol, heated to 80°C, and stirred until the reaction was complete. Cool to room temperature, add a small amount of water, extract with ethyl acetate, combine the organic layers, wash with water, dry, and distill off the solvent to obtain a colorless transparent liquid, namely ethyl 5-methyl-2-hexenoate, with a yield of 97%. The water phase is evaporated to recover DES, which can be reused.

¹ H NMR (400MHz, CDCl ₃ )δ:6.46(m,1H),5.77(s,1H),4.09-4.18(m,2H),1.51-1.58(t,2H),1.22-1.24(m,1H ),0.84-0.87(d,6H).

Example 3 Synthesis of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester:

Add 1.4g (1mol) choline chloride and 1.2g (2mol) urea to a dry three-necked flask, heat up to 80°C, stir magnetically until a colorless transparent liquid is obtained, DES3 (choline chloride-urea), cool to Room temperature; add 0.861g (1mol) ethyl 5-methyl-2-hexenoate and 0.404g (1.2mol) nitromethane, heat up to 80°C, stir until the reaction is complete, then cool to room temperature. Add a small amount of water, extract with ethyl acetate, wash the organic layers with water, dry, evaporate the solvent to obtain a light yellow transparent liquid, 3-nitromethylene-5-methyl-hexanoic acid ethyl ester, the yield is 97%, water Phase evaporation recovers DES, which can be reused.

¹ H NMR (400MHz, CDCl ₃ )δ:4.11-4.16(d,2H),4.02-4.07(m,2H),3.8-3.3(m,2H),3.30(s,1H),1.97(s,1H ),1.21-1.23(m,2H),1.18-1.20(m,3H),0.83-0.85(d,6H).

Example 4 Synthesis of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester:

Add 1.4g (1mol) choline chloride and 1.2g (2mol) urea to a dry three-necked flask, heat up to 80°C, stir magnetically until a colorless transparent liquid is obtained, DES3 (choline chloride-urea), cool to Room temperature; add 0.861g (1mol) ethyl 5-methyl-2-hexenoate and 0.404g (1.2mol) nitromethane, heat up to 70°C, stir until the reaction is complete, then cool to room temperature. Add a small amount of water, extract with ethyl acetate, wash the organic layers with water, dry, evaporate the solvent to obtain a light yellow transparent liquid, 3-nitromethylene-5-methyl-hexanoic acid ethyl ester, the yield is 93%, water Phase evaporation recovers DES, which can be reused.

¹ H NMR (400MHz, CDCl ₃ )δ:4.11-4.16(d,2H),4.02-4.07(m,2H),3.8-3.3(m,2H),3.30(s,1H),1.97(s,1H ),1.21-1.23(m,2H),1.18-1.20(m,3H),0.83-0.85(d,6H).

Example 5 Synthesis of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester:

Add 1.4g (1mol) choline chloride and 1.2g (2mol) urea to a dry three-necked flask, heat up to 80°C, stir magnetically until a colorless transparent liquid is obtained, DES3 (choline chloride-urea), cool to Room temperature; add 0.861g (1mol) ethyl 5-methyl-2-hexenoate and 0.336g (1mol) nitromethane, heat up to 80°C, stir until the reaction is complete, then cool to room temperature. Add a small amount of water, extract with ethyl acetate, wash the organic layers with water, dry, evaporate the solvent to obtain a light yellow transparent liquid, 3-nitromethylene-5-methyl-hexanoic acid ethyl ester, the yield is 91%, water Phase evaporation recovers DES, which can be reused.

¹ H NMR (400MHz, CDCl ₃ )δ:4.11-4.16(d,2H),4.02-4.07(m,2H),3.8-3.3(m,2H),3.30(s,1H),1.97(s,1H ),1.21-1.23(m,2H),1.18-1.20(m,3H),0.83-0.85(d,6H).

Reusability of DES

Taking the synthesis of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester as an example, the reusability of DES was investigated. 0.861g (1mol) 5-methyl-2-hexenoic acid ethyl ester, 0.404g (1.2mol) nitromethane, 80 ℃ of reaction temperature, TLC monitors to reaction completely, after reaction finishes, will contain the filtrate of DES, reduce Pressure steamed to remove water, can be used for the next experiment. The results are shown in Figure 4.

It can be seen from Fig. 4 that the yield of 3-nitromethylene-5-methyl-hexanoic acid ethyl ester decreased slightly when DES was reused 5 times, all of which were above 95%, indicating better reusability.

Claims (9)

1. The synthesis method of the pregabalin intermediate 3-nitromethylene-5-methyl-ethyl caproate is characterized by comprising the following steps of:

the isovaleraldehyde and malonic acid react in a choline chloride-urea eutectic solvent to obtain 5-methyl-2-hexenoic acid;

reacting 5-methyl-2-hexenoic acid with absolute ethyl alcohol in a choline chloride-methanesulfonic acid eutectic solvent to obtain 5-methyl-2-hexenoic acid ethyl ester;

and reacting the 5-methyl-2-hexenoic acid ethyl ester with nitromethane in a choline chloride-urea eutectic solvent to obtain the 3-nitromethylene-5-methyl-ethyl caproate.

2. The method of claim 1, wherein the reaction formula is:

。

3. the method of claim 1, wherein the molar ratio of isovaleraldehyde to malonic acid is 1 (1.0 to 1.2).

4. The process according to claim 1, wherein the molar ratio of 5-methyl-2-hexenoic acid to absolute ethanol is 1 (1.0-1.2).

5. The process according to claim 1, wherein the molar ratio of ethyl 5-methyl-2-hexenoate to nitromethane is 1 (1.0-1.2).

6. The method according to claim 1, wherein the choline chloride-urea eutectic solvent is obtained by heating and stirring choline chloride and urea in a molar ratio of 1:2, or by recovering from the reaction of isovaleraldehyde and malonic acid, or by recovering from the reaction of ethyl 5-methyl-2-hexenoate and nitromethane.

7. The method according to claim 1, wherein the choline chloride-methanesulfonic acid eutectic solvent is obtained by heating and stirring choline chloride and methanesulfonic acid in a molar ratio of 1:2 or by recovering 5-methyl-2-hexenoic acid from a reaction with absolute ethanol.

8. The method of claim 1, comprising the steps of:

the first step: adding Amol choline chloride and B mol urea into a dry three-neck flask, heating to 80 ℃, magnetically stirring to obtain colorless transparent liquid, namely a choline chloride-urea eutectic solvent DES1, and cooling to room temperature; then adding C mol of isovaleraldehyde and D mol of malonic acid, wherein A is B, C is D=1:2:1, (1.0-1.2), heating to 80 ℃, stirring for reaction, and monitoring by TLC until the reaction is complete; after the reaction is finished, cooling to room temperature, adding a small amount of water, extracting with ethyl acetate, washing an organic layer with water, drying, and evaporating the solvent to obtain colorless transparent liquid, namely 5-methyl-2-hexenoic acid; the DES1 is recovered by water phase evaporation and can be reused;

and a second step of: e mol of choline chloride and F mol of methanesulfonic acid are added into a dry three-neck flask, the temperature is raised to 80 ℃, the mixture is magnetically stirred to obtain colorless transparent liquid, namely a choline chloride-methanesulfonic acid eutectic solvent DES2, and the mixture is cooled to room temperature; adding G mol of 5-methyl-2-hexenoic acid and H mol of absolute ethyl alcohol, wherein E is F, G is H=1:2:1, (1.0-1.2), heating to 80 ℃, and stirring to react until the reaction is complete; cooling to room temperature, adding a small amount of water, extracting with ethyl acetate, combining organic layers, washing with water, drying, and evaporating to remove solvent to obtain colorless transparent liquid, namely 5-methyl-2-hexenoic acid ethyl ester; the water phase is evaporated to recover DES, and the DES can be reused;

and a third step of: adding I mol of choline chloride and J mol of urea into a dry three-neck flask, heating to 80 ℃, magnetically stirring to obtain colorless transparent liquid, namely a choline chloride-urea eutectic solvent DES3, and cooling to room temperature; adding Kmol of 5-methyl-2-hexenoic acid ethyl ester and Lmol of nitromethane, wherein the ratio of I to J to K to L=1 to 2 to 1, (1.0-1.2), heating to 80 ℃, stirring to react completely, and cooling to room temperature; adding a small amount of water, extracting with ethyl acetate, washing the organic layer with water, drying, and evaporating to remove the solvent to obtain light yellow transparent liquid, namely 3-nitromethylene-5-methyl-ethyl caproate.

9. The method according to claim 8, wherein distilled water is added after the completion of the first, second or third steps, the distilled water being 1.5 times that of the solvent.

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